tbuckley/cabot-search huggingface dataset:
Abstract 564: Targeting axonal guidance with anti-ROBO1 CAR T cells: A new therapeutic strategy for malignant brain cancer
Authors: Sheila Kumari Singh, Chirayu R. Chokshi, Benjamin Brakel, Martin A. Rossotti, Chitra Venugopal, Sabra Salim, Kevin Henry
Journal: Cancer Research (2022)

Abstract No standardized treatment exists for patients with recurrent glioblastoma (GBM). Given the aggressive nature of the disease and difficulty in modeling tumor recurrence, minimal efforts have been made to design rational therapies against it. The roundabout guidance receptor 1 (ROBO1) protein is involved in axonal guidance during neurodevelopment and is aberrantly upregulated in glioma where it mediates glioma cell migration. Here, we present that ROBO1 is highly expressed on the surface of malignant and treatment-refractory brain tumor initiating cells (BTICs), prompting the development of an anti-ROBO1 CAR-T cell therapy. Using the binding region of a single-domain antibody targeting ROBO1, we developed second-generation anti-ROBO1 CAR-T cells specific and effective against ROBO1-expressing BTICs. Upon antigen exposure, anti-ROBO1 CAR-T cells upregulated markers of activation and degranulation. Additionally, treatment of orthotopic and patient-derived brain tumor xenograft models with anti-ROBO1 CAR-T cells resulted in reduced tumor burden and prolonged survival, demonstrating the therapy’s therapeutic potential for treating neoplastic brain malignancies. Citation Format: Sheila Kumari Singh, Chirayu R. Chokshi, Benjamin Brakel, Martin A. Rossotti, Chitra Venugopal, Sabra Salim, Kevin Henry. Targeting axonal guidance with anti-ROBO1 CAR T cells: A new therapeutic strategy for malignant brain cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 564.
Abstract 3032: Selenoprotein Sepp1 determines cysteine dependence in pancreatic cancer
Authors: Arslan Amer, Tahiyat Alothaim, Xiaohu Tang
Journal: Cancer Research (2022)

Abstract Pancreatic cancer (PaCa) represents the fourth leading cause of overall cancer death, despite its relatively low incidence compared to other malignancies (Lung, prostate, breast, etc.). Approximately 57,600 people were estimated to be diagnosed with pancreatic cancer in the USA, and 47,050 were estimated to die of the disease in 2020 reported by The American Cancer Society. Novel effective therapeutic strategies are urgently needed. Metabolic changes are typically associated with tumor development to support fast cell proliferation and malignant transition. Such metabolic deregulations differentiate tumor cells from normal cells and act as potential targets of anticancer therapies. Previous studies have shown cysteine dependence often presents in various cancers, since cysteine metabolism supplies glutathione - an important substrate for the cellular reactive oxygen species (ROS) cleanup cycle. Studies in breast and kidney cancers have shown that such cysteine-dependence is a prominent feature in the cancer subtypes with a mesenchymal cell phenotype, instead of in the epithelial subtype. We found that cysteine dependence exists in pancreatic cancer as well. Mesenchymal PaCa cells, in contrast to the epithelial tumor cells, appear to be more sensitive to cysteine depletion with extensive induction of ferroptosis, a programmed cell death pathway involving iron and lipid peroxidation. Gene expression analysis revealed the selenium transporter protein Sepp1 to be absent in the mesenchymal PaCa cells. Knockdown of Sepp1 expression in cysteine-independent cells renders cells dependent on cysteine. Selenium is a micronutrient required for the synthesis of selenoproteins including GPX4 and Sepp1. The addition of selenium alleviated cell reliance on cysteine and caused resistance to GPX4 inhibitor-induced ferroptosis. We observed that Sepp1 regulates the thioredoxin pathway to rescue the cells under the glutathione deficiency. Interestingly, the conditioned media assay also revealed that Sepp1 protects cells from ROS stress by a symbiotic mechanism. Our findings suggest that Sepp1 could serve as a biomarker of tumor cysteine-dependency and a potential molecular target for therapeutic strategies to overcome drug resistance in pancreatic cancer. Citation Format: Arslan Amer, Tahiyat Alothaim, Xiaohu Tang. Selenoprotein Sepp1 determines cysteine dependence in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3032.
Abstract 3099: Biological evaluation of a novel AKR1C3 inhibitor in patient-derived prostate cancer cell line and xenograft models
Authors: Joy C. Yang, Shu Ning, Hans Adomat, Martin Gleave, Allen Gao, Christopher P. Evans, Chengfei Liu
Journal: Cancer Research (2022)

Abstract INTRODUCTION AND OBJECTIVES: Prostate cancer is a highly heterogeneous cancer type with distinct genomic and phenotypic characteristics that drive tumorigenesis and the differential response to drug therapies. A limit number of prostate cancer cell lines and patient-derived xenograft (PDX) models hinders research to improve disease outcome. Some currently available PDX models were derived from the primary tumor samples are insufficient to recapitulate the clinical response at more advanced stages. In this study, we developed patient-derived models from patients with advanced disease and evaluated a novel AKR1C3 inhibitor in these models. METHODS: Samples received from our Pathology Biorepository Shared Resource were divided into four groups and subjected to pathological staining, RNA extraction, xenografting in NSG mice via renal capsule and subcutaneous implantation in SCID mice and conditional reprogramed cultures (CRCs) or organoid culturing. The AKR1C3 inhibitor PB was modified from celecoxib. Androgen receptor (AR), AR-V7 and AKR1C3 expression were determined by western blot. The effects of the AKR1C3 inhibitor on enzalutamide sensitivity were characterized by growth assay and colony formation assay. RESULTS: Eight PDX models have been developed from prostate cancer patients with high Gleason score and/or at the castration-resistant stages. Among the PDX models, one spontaneous indefinite cell line PS1172 was established. Early passage CRCs showed the epithelial morphology with AR positive expression. Through serially passaging PS1172 PDX with castration in SCID mice, the castration resistant cell line 1172CR was re-cultured from castration-resistant PS1172 PDX tumors. 1172CR cells were resistant to enzalutamide treatment and expressed high level of AKR1C3 and AR-V7. A novel AKR1C3 inhibitor (PB) which displayed superior potential to inhibit AKR1C3 activity and suppress enzalutamide resistant prostate cancer cell growth was tested in these models. At the same dose, PB significantly suppressed 1172CR cell growth and colony formation compared to indomethacin and enzalutamide. PB also significantly suppressed AR/AR-V7 protein expression compared to indomethacin in 1172CR cells. CONCLUSION: PS1172 and castration-resistant 1172CR cells are novel models with significant characteristics such as AR-V7 and AKR1C3. These novel prostate cancer models are ideal for small molecule testing and resistant mechanism investigating. Citation Format: Joy C. Yang, Shu Ning, Hans Adomat, Martin Gleave, Allen Gao, Christopher P. Evans, Chengfei Liu. Biological evaluation of a novel AKR1C3 inhibitor in patient-derived prostate cancer cell line and xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3099.
Abstract 2573: PI3K/AKT/mTOR pathway and CDK4/6 inhibitors efficiently inhibit cell growth of HPV-positive and HPV-negative head and neck squamous cell carcinoma <i>in vitro</i>
Authors: Imke Demers, Femke Verhees, Dion Leegemaate, Robin Jacobs, Ann Hoeben, Frank Hoebers, Bernd Kremer, Ernst-Jan Speel
Journal: Cancer Research (2022)

Abstract Introduction: Both HPV-positive and -negative head and neck squamous cell carcinoma (HNSCC) often show activation of the PI3K/AKT/mTOR pathway, due to, amongst others, PI3KCA mutations, PTEN loss, or receptor tyrosine kinase activation. In HPV-negative tumors, CDKN2A (p16) inactivation or CCND1 (cyclin D1) amplification frequently occurs resulting in sustained cyclin dependent kinase (CDK) 4/6 activation. The aim of our study was to investigate the efficacy of PI3K/AKT/mTOR pathway inhibitors (PI3Ki) (alpelisib, buparlisib and gedatolisib) and CDK4/6 inhibitors (CDKi) (palbociclib and ribociclib) in HPV-positive and -negative HNSCC cell lines. Methods: The efficacy of the inhibitors was assessed using MTT assays and changes in PI3K and Cyclin D1/CDK pathway protein expression were determined by Western blotting. Cell cycle analysis was performed with flow cytometry and apoptosis was assessed by Annexin-V staining. Changes in cell metabolism were assessed by Seahorse XF assays. Results: Both HPV-positive and -negative HNSCC cell lines were highly sensitive to the PI3Ki (Gedatolisib, IC50 5-30 nM &amp;gt; Buparlisib, IC50 0.6-3.6 µM &amp;gt; Alpelisib, IC50 3-23 µM). In general, PI3Ki decreased pathway activity, resulted in moderate cell cycle arrest and apoptosis, and decreased oxidative and glycolytic metabolism. CDKi were particularly effective in blocking HPV-negative cell line growth (Palbociclib, IC50 0.5-2 µM &amp;gt; Ribociclib, IC50 4-7 µM). CDK inhibition showed decreased pRb expression and G1 cell cycle arrest, whereas apoptosis was not induced. Conclusion: PI3Ki and CDKi efficiently inhibit their respective pathways and HNSCC cell growth in vitro, the latter only in HPV-negative cell lines. Whereas PI3Ki especially show an effect on oxidative and glycolytic metabolism, CDKi particularly lead to cell cycle arrest. Further research should elucidate whether these inhibitors may be effective therapeutic agents in HNSCC patients. Citation Format: Imke Demers, Femke Verhees, Dion Leegemaate, Robin Jacobs, Ann Hoeben, Frank Hoebers, Bernd Kremer, Ernst-Jan Speel. PI3K/AKT/mTOR pathway and CDK4/6 inhibitors efficiently inhibit cell growth of HPV-positive and HPV-negative head and neck squamous cell carcinoma in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2573.
Abstract 6241: Macc1 regulates breast cancer progression and metastasis via remodeling tumor immune microenvironment
Authors: Hye-Youn Son, Woo Hang Heo, Song Bin Li, Mingji Quan, Yu Jeong Her, Kyu-Jin Lee, Ju Hee Kim, Han-Byoel Lee, Wonshik Han, Hyeong-Gon Moon
Journal: Cancer Research (2022)

Abstract Although the established cancer cell lines exhibit less degrees of intratumoral heterogeneity when compared to human solid tumors, studies have suggested that, even within the same cancer cell line, substantial degree of heterogeneity may exist. In this study, we have performed single cell cloning experiment using 4T1 mouse mammary carcinoma cell line and compared the phenotypes of different clones. When compared to the parental 4T1 cell line, one clone (C12) showed markedly different phenotype by exhibiting less aggressive features in vitro and significantly slower tumor growth and metastasis in vivo. The tumor tissue of the C12 showed significant alteration in immune microenvironment as higher number of recruited immune cells including T and B cells. RNA sequencing of the C12 clones and parental 4T1 cells identified Macc1 as a significantly up-regulated gene in parental 4T1 cells. Metastasis-associated colon cancer 1 (MACC1) has been associated with poor prognosis and the promotion of metastasis within several types of cancer, especially colon cancer. The gene encoding the hepatocyte growth factor (HGF) receptor, MET, is a transcriptional target of MACC1. Next, we established Macc1-silenced 4T1 cells using the parental 4T1 cells and observed that Macc1-silencing resulted in a similar phenotype seen in the C12 clone; decreased cell proliferation and migration in vitro and slow tumor growth and metastasis in vivo. To mimic the metastasis in vitro, intravasation was determined as which tumor cells were co-cultured with HUVEC, human umbilical vein endothelial cells. We discovered tumor cell penetration into HUVEC cells was blocked in Macc1-silencing 4T1 group. According to CD45, CD3, and CD19 immunohistochemistry, we also defined immune cells, especially T and B cells, were highly infiltrated in Macc1-silencing tumor like as C12 clone tumor. These results were also reconstructed in EMT6, another TNBC mouse cell line model. In this study, we show that MACC1 can regulate tumor progression and metastasis by remodeling of immune microenvironment. Citation Format: Hye-Youn Son, Woo Hang Heo, Song Bin Li, Mingji Quan, Yu Jeong Her, Kyu-Jin Lee, Ju Hee Kim, Han-Byoel Lee, Wonshik Han, Hyeong-Gon Moon. Macc1 regulates breast cancer progression and metastasis via remodeling tumor immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6241.
Abstract 6396: Detection of stemness and EMT in response to radiation in glioblastoma and ovarian cancer cells
Authors: Aaron Keniston, Alondra Enciso, Yeonkyu Jung, Ashley Antonissen, Ryan Fuller, Ann Morcos, Antonella Bertucci, Marcello Vazquez, Juli Unternaehrer
Journal: Cancer Research (2022)

Abstract Tumor recurrence and metastasis contribute to the poor prognosis of ovarian cancer (OC) and glioblastoma multiforme (GBM). The aggressiveness of GBM and OC during recurrence creates a need to identify potential therapeutic targets. The cancer stem cell (CSC)-like phenotype and epithelial mesenchymal transition (EMT) have been shown to contribute to cancer aggressiveness, which makes CSCs and EMT viable targets for therapeutic intervention. EMT is a normal process during development and wound healing, but its reactivation in cancer cells contributes to metastasis. To detect CSC phenotypes in live cells without the use of antibodies, we are analyzing core stem cell transcription factors in which a SOX2/OCT4 response element, designated as SORE6, regulates a GFP reporter system. Also, to detect EMT we are using a GFP based reporter regulated by Zeb1 3’ UTR, a common EMT marker. Our aim is to detect changes in stemness and EMT in response to proton and photon ionizing radiation (IR). We hypothesize that proton and photon IR have similar effects on aggressiveness in OC and GBM. To investigate this, 2 GBM cancer cell lines, 1 breast cancer cell line, 1 OC cell line, and two patient derived samples were exposed to 0, 1, 2, 4 and 8Gy of 250 MeV proton and 6 MeV photon beams. 72 hours post IR exposure, flow cytometry analysis quantified reporter activity. We found an increase in stemness as radiation dosage increased in most cell lines. Results suggest that proton radiation increases stemness more than photon exposure. Citation Format: Aaron Keniston, Alondra Enciso, Yeonkyu Jung, Ashley Antonissen, Ryan Fuller, Ann Morcos, Antonella Bertucci, Marcello Vazquez, Juli Unternaehrer. Detection of stemness and EMT in response to radiation in glioblastoma and ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6396.
Abstract 4017: Defining cell type-specific pathways in both cancer and tumor-microenvironment cells that impact survival of clear cell renal carcinoma patients
Authors: Ilya Strunilin, Yige Wu, Ruiyang Liu, Wagma Caravan, Feng Chen, Li Ding
Journal: Cancer Research (2022)

Abstract Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer, with 5-year mortality of 25%. The molecular landscape of ccRCC has been elucidated by a number of next generation sequencing studies and complemented by recent global proteome and phosphoproteome results. However, a limitation of such studies is the mixture of signals from distinct cell populations, presenting challenges to subsequent interpretation. As a remedy, single nuclei RNA-seq (snRNA-seq) is able to dissect distinct cell populations and map their differential expression patterns. Using snRNA-seq from 30 ccRCC tumor samples, we identified distinct genetic pathways associated with survival in the TCGA patient cohort (525 patients) in multiple cell types, including immune and stromal components. Prognostic value of pathways was confirmed in an independent cohort with 130 patients. Multiple cancer cell-specific pathways were related to metabolism, suggesting that certain metabolites are less abundant in high-risk tumors. Using data from two independent large-scale metabolism ccRCC studies, we found metabolites’ levels changing in accordance with our predictions, when comparing low-risk to high-risk ccRCC tumors. Citation Format: Ilya Strunilin, Yige Wu, Ruiyang Liu, Wagma Caravan, Feng Chen, Li Ding. Defining cell type-specific pathways in both cancer and tumor-microenvironment cells that impact survival of clear cell renal carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4017.
Abstract 2200: Multilineage plasticity in prostate cancer through expansion of stem-like luminal epithelial cells with elevated inflammatory signaling
Authors: Samir Zaidi, Jimmy Zhao, Joseph Chan, Roudier Martine, Kristine Wadosky, Anuradha Gopalan, Wouter Karthaus, Philip Watson, Lawrence True, Peter Nelson, Howard Scher, Michael Morris, Michael Haffner, David Goodrich, Dana Pe'er, Charles Sawyers
Journal: Cancer Research (2022)

Abstract Lineage plasticity is a well-established mechanism of resistance to targeted therapies in lung and prostate cancer, where tumors transition from adenocarcinoma to small-cell or neuroendocrine carcinoma. Single-cell analysis of a cohort of late stage castration-resistant human prostate cancers (CRPC) revealed a greater degree of plasticity than previously appreciated, with multiple distinct neuroendocrine (NEPC), mesenchymal (EMT-like), and other subpopulations detected within single biopsies. To explore the steps responsible for initiation of this process, we utilized two genetically engineered mouse models of prostate cancer that recapitulate progression from adenocarcinoma to neuroendocrine disease. Time course studies reveal expansion of stem-like luminal epithelial cells (Sca1+, Psca+, called L2) that, based on trajectories, gave rise to at least 4 distinct subpopulations, NEPC (Ascl1+), POU2F3 (Pou2f3+), TFF3 (Tff3+) and EMT-like (Vim+, Ncam1+). Such populations are also seen in human prostate and small cell lung cancers. Furthermore, transformed L2-like cells express stem-like and gastrointestinal endoderm-like transcriptional programs, indicative of reemerging developmental plasticity programs, as well as elevated Jak/Stat, interferon, and FGF pathways. Strikingly pharmacologic inhibition of Jak/Stat and FGFR results in reversal of plasticity states and subsequent sensitivity to androgen receptor inhibitors (ARSIs). In sum, while the magnitude of multilineage heterogeneity, both within and across patients, raises considerable treatment challenges, the identification of highly plastic luminal cells as the likely source of this heterogeneity provides a target for more focused therapeutic intervention. Citation Format: Samir Zaidi, Jimmy Zhao, Joseph Chan, Roudier Martine, Kristine Wadosky, Anuradha Gopalan, Wouter Karthaus, Philip Watson, Lawrence True, Peter Nelson, Howard Scher, Michael Morris, Michael Haffner, David Goodrich, Dana Pe'er, Charles Sawyers. Multilineage plasticity in prostate cancer through expansion of stem-like luminal epithelial cells with elevated inflammatory signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2200.
Abstract 5651: Characterization the mechanistic role of the proapoptotic receptor XEDAR and its therapeutic potential in TNBC
Authors: Chih-Yi Lin, Chung-Jen Yu, Chih-Yang Wang, Kai-Jun Liu, Jiun-I Lai
Journal: Cancer Research (2022)

Abstract Breast cancer is one of the most common cancers and a leading cause of death in women worldwide. Among these subtypes, triple negative breast cancer (TNBC) has the worst prognosis, with a dismal outcome especially in metastatic disease. Metastatic TNBC treated with conventional chemotherapy has a median overall survival (OS) of ~ 18 months. The addition of checkpoint inhibitors extend the median OS to more than 2 years in PD-L1 positive patients, but ultimately most patients succumb to the disease. Currently TNBC still poses as a clinical unmet need, and further understanding of the cancer biology may shed light in improving therapeutics against this deadly disease. Apoptosis, or programmed cell death, is a crucial function for cell homeostasis. The ability to evade or circumvent apoptosis is an important hallmark of cancer cells. X-linked ectodermal dysplasia receptor (XEDAR), a cell membrane receptor that binds to the pro-apoptotic ligand EDA-A2, is a member of the TNF receptor family and has been reported to be downregulated in breast cancer cells. XEDAR has been shown to induce downstream apoptosis by binding to EDA-A2, by a mechanism similar to extrinsic apoptotic pathway. By interrogating clinical databases and cross comparison using TCGA, CCLE, and other breast cancer datasets, we discover XEDAR as substantially downregulated in TNBC. Transcription profile analysis between different XEDAR expressing profiles uncovered novel pathways that could be potentially targeted for TNBC treatment. RNA-seq profiling in XEDAR overexpressing TNBC cells were cross compared with aforementioned discovered pathways. Vulnerable pathways including angiogenesis were discovered as possible therapeutic targets. As a proof of concept, we combined angiogenesis inhibitors with EDA-A2 ligand treatment in XEDAR overexpression TNBC cells and observed synergistic effects for combination. Our study uncover XEDAR as a potential target for further treatment in TNBC, which remains to be further validated in preclinical and clinical studies. Citation Format: Chih-Yi Lin, Chung-Jen Yu, Chih-Yang Wang, Kai-Jun Liu, Jiun-I Lai. Characterization the mechanistic role of the proapoptotic receptor XEDAR and its therapeutic potential in TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5651.